Acute BH4 depletion leads to a loss of myocardial protection conferred by cardiac‐specific overexpression of inducible nitric oxide synthase in mice (547.11)

Abstract

Many studies have shown that cardiac overexpression of NOS enzymes can lead to myocardial protection against ischemia/reperfusion (I/R) injury. However, none of these studies experiment with modulating BH4 levels. Because adequate BH4 levels lead iNOS to produce nitric oxide and inadequate BH4 levels lead iNOS to produce damaging superoxide, we hypothesized that depletion of BH4 in a model of constitutive iNOS expression would lead to a loss of iNOS function and diminished recovery of post‐ischemic myocardial contractility. The study involved two groups of iNOS TG mice: untreated mice and treated mice. Treated mice received 21 days of BH4 depletion diet using food with GTP cyclohydrolase inhibitor 2,4‐舃Diamino‐舃6‐舃hydroxypyrimidine (DAHP). The 21 day DAHP treatment led to a roughly 65% myocardial depletion of BH4 as measured by HPLC. Hearts from these two groups were used in isolated heart experiments and were subjected to 30’ of ischemia and 60’ of reperfusion. Compared to untreated mice, DAHP‐treated mice had significantly less recovery of rate pressure product, left ventricular developed pressure, and significantly more elevated end diastolic pressure at 30 and 60’ of reperfusion. This work shows the importance of adequate BH4 levels in protection against myocardial I/R, especially in the context of NOS overexpression.Grant Funding Source: 00000784